WO1999011266A1

WO1999011266A1 - Multiple sclerosis remedies

Info

Publication number: WO1999011266A1
Application number: PCT/JP1998/003897
Authority: WO
Inventors: Hiroshi Okazaki; Ko Tsutsui; Masakazu Adachi; Takao Taki
Original assignee: Otsuka Pharmaceutical Co., Ltd.
Priority date: 1997-09-04
Filing date: 1998-09-01
Publication date: 1999-03-11
Also published as: AU8888798A; JP4120713B2; JPH1179995A

Abstract

Multiple sclerosis remedies each comprising an effective amount of at least one member selected from among carbostyril derivatives represented by general formula (1) and salts thereof and a pharmaceutically acceptable carrier, which can ameliorate various clinical symptoms of multiple sclerosis and are effective in the prevention of recurrence of multiple sclerosis and the treatment thereof, wherein R is benzoyl which is optionally substituted with lower alkoxy on the phenyl ring; and the carbon-carbon bond between the 3- and 4-positions of the carbostyril skeleton represents a single or double bond.

Description

Specification

Treatment of multiple sclerosis 剂 Technology

The present invention relates to a therapeutic agent for multiple sclerosis, comprising a specific carbostyril derivative or a salt thereof as an active ingredient. Background technology

Multiple sclerosis is a demyelinating disease of the central nervous system of unknown cause. It mainly affects young adults and multifocal demyelinating lesions occur in the central nervous system, such as the brain, spinal cord, and optic nerve, in a multiphasic manner. Progressive intractable neurological disease characterized by spatial multipleness.

Clinical symptoms can be any disorder of the central nervous system, but visual impairment due to disorders of the optic nerve and spinal cord, motor paralysis walking disorder, numbness, abnormal sensation, sensation, eye pain, etc. . In addition, diplopia may occur in brainstem disorders and ataxia may occur in cerebellar lesions. The most common age is between 20 and 40 years. The etiology of the multiple sclerosis is unknown to date and there are autoimmune and viral theories, but none of them has been conclusive. As described above, the diagnosis of multiple sclerosis mainly depends on clinical characteristics because the etiology is unknown and there are no specific test abnormalities as described above. Currently used diagnostic criteria are the multiple sclerosis (MS) diagnostic criteria by the Ministry of Health and Welfare specific disease “multiple sclerosis” research group, and Poser (CM, (1983)). These MS diagnostic criteria are known. Recently, diagnosis by MRI has been considered useful. As the findings of this disease by the diagnosis is that T ₂ margin oval in enhanced image is relatively clear, high intensity area lesions (bra one click) is observed in cerebral white matter and brain stem.

Treatment of multiple sclerosis can be divided into treatment for the etiology and symptomatic treatment for various CNS symptoms. For the former, the etiology is unknown at present, so immunosuppressive drugs and anti-inflammatory drugs are used for its treatment, but its efficacy is difficult to determine. In the acute phase, corticosteroids are used, and when the symptoms are more acute and severe, pulsed steroids are administered. Treatment for the chronic phase mainly consists of symptomatic treatment of neuropathy and rehabilitation.

Recently, it has been reported that treatment with IFN-1 / 3 (IFN- / 3) reduces the number of relapses of multiple sclerosis as a preventive therapy for relapse and treatment for intractable cases. To the United States The IFN —; S has been approved. However, a treatment method for multiple sclerosis has not yet been established, and the development of a drug having a preventive effect on the recurrence of multiple sclerosis and a therapeutic effect on various clinical symptoms has been developed in the art. It is desired.

Therefore, an object of the present invention is to develop a drug having a preventive effect on multiple sclerosis and a therapeutic effect on various clinical symptoms, which are desired in the art.

As a result of repeated studies for the above purpose, the present inventor found that a carbostyril derivative represented by the following general formula (1) and a salt thereof, which had been previously developed as an active ingredient for cardiotonic agents, had a high frequency of The present inventors have found the fact that they are effective as therapeutic agents for keratosis, and have completed the present invention. Disclosure of the invention

That is, the present invention provides the following general formula (1):

N-R [In the formula, R represents a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring. The carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton indicates a single bond or a double bond. ]

A therapeutic agent for multiple sclerosis, characterized by containing an effective amount of at least one selected from the carbostyril derivative represented by the formula (I) and a salt thereof, and a pharmaceutically acceptable carrier. Things.

The present invention also provides a multiple sclerosis, comprising administering to a patient at least one effective amount selected from the carbostyril derivative represented by the above general formula (1) and a salt thereof. It is concerned with the treatment of the disease.

Furthermore, the present invention relates to the use of at least one kind selected from the carbostyril derivative represented by the above general formula (1) and a salt thereof for the production of a therapeutic agent for multiple sclerosis. is there. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the results of a test performed according to Pharmacological Test Example 1, and shows the effect of the compound of the present invention in a rat experimental allergic encephalomyelitis model.

Figure 2 shows the results of tests performed according to Pharmacological Test Example 1. 4 is a graph showing the effect of the compound of the present invention on the average integrated clinical score in a rat experimental allergic encephalomyelitis model.

FIG. 3 is a graph showing the results of a test performed in accordance with Pharmacological Test Example 1, and shows the effect of the compound of the present invention on body weight change in a rat experimental allergic encephalomyelitis model. BEST MODE FOR CARRYING OUT THE INVENTION

According to the present invention, in the general formula (1), R has 1 to 3 straight or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring. The therapeutic agent for multiple sclerosis, which is a benzoyl group, is also provided.

Further, according to the present invention, the carbostyryl derivative is 6- [4— (3,4-dimethoxybenzoinole) -11-piperazinyl] 13,4—dihydronorrebostyryl Alternatively, the above agent for treating multiple sclerosis, which is a salt thereof, is also provided.

In the present invention, the carbostyril derivative represented by the above general formula (1) and a salt thereof used as an active ingredient for treating multiple sclerosis are described, for example, in Japanese Patent Publication No. As described in the official gazette and U.S. Pat.No. 4,415,572, it is a known substance and its production method is For example, it is described in the above publication. Further, these documents also describe that the carbostyril derivative represented by the above general formula (1) and a salt thereof are useful as a cardiotonic agent.

In addition, the carbostyril derivative and one of its salts have also been demonstrated to improve hemodynamic parameters and exercise tolerance in patients with depressive heart failure [Inoue et al. 1. , Heart Vessels, 2, 166-171 (1986); Sasayama et a 1., Heart Vessels, 2, 23-28 (1986); Feldman et al., Am. Heart J., Π6, 771-777 (1988). ]. The mechanism related to the inotropic action of the above carbostyril derivatives is based on the reduction of the rhodium current CI ijima et al., J. Pharmacol. Exp. Ther, 240, 657-662 (1987)], Mild suppression of phospho-gesterase and increased inward flow of calcium currents (Yatani et al., J. Cardiovasc. Pharmacol., 13, 81 2-819 (1989); Taira et al. , Arzneimi ttelf orshung, March 4, 347-355 (1984)].

The above-mentioned carbostyril derivative further comprises TNF-a, IL-6, IL-11; 8, IL-11 by peripheral blood mononuclear cell (PBMC) stimulated by lipopolysaccharide saccharide (LPS). — Bush, F. et al., Eur. J. Clin. Ph, which have been reported to suppress the production of various cytokines, including 2 and IFN-y. armacol., 42, 629 ^ 634 (1992); Maruyama et al., Biochem. Biophys. Res.Commu., 195, 1264-1271 (1993); Shioi, T. et al., Life Sciences, 54 ( 1), PL11-16C199 4); Matsumori, A. et al., Circulation, 89 (3), 955-958 (1994)]

Furthermore, it has also been reported that the above carbostyril derivative has an effect of improving virus-induced myocardial injury and inhibiting natural killer cells (NK cells) at the time of improving the myocardial injury. C Matsui S , et al., J. Clin. Invest., 94. 1212-1217 (1994)]. In addition to the above effects, the carbostyryl derivative has also been reported to have an apoptosis-regulating effect. Based on this effect, it is possible to treat cancer and suppress cancer metastasis, autoimmune diseases, and viruses. Its usefulness for diseases, etc. has also been reported [European Patent Publication EP0552373; Nakai et a 1., Jpn. J. Cancer Res., Abstruct, and Proc. Jpn. Cancer Assoc., 581 (1993) ) Maruyama et al., Biochem. Biophys. Res. Com j_95, while only 1264- 1271 (1993)] _0, the carbo steel Li Le derivative or a salt thereof represented by the general formula (1), cormorants described above There is no report that it has an effect of suppressing clinical symptoms of severe multiple sclerosis.

Carbostyril derivative, which is the active ingredient of the drug of the present invention, More specifically, each group represented by the above general formula (1) can be exemplified by the following groups.

That is, the lower alkoxy group is preferably a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butyl. Examples include toxic, pentyloxy, and hexyloxy groups.

Benzoyl groups that may have a lower alkoxy group as a substituent on the phenyl ring include, for example, benzoyl, 2-methoxybenzoisole, 3-methoxybenzoyl, and 4-methoxy. Cienzo Zinore, 2—Etoxy Benzinole, 3—Etoxy Benzinore, 41—Ethoxy Benzinole, 3—Isopropoxybenzoyl, 4—butoxy Benzoinole, 21-pentinoleoxybenzole, 3 — hexinoleoxybenzole, 3, 4 — dimethoxybenzoinole, 2, 5 — dimethoxybenzoinole, 3, 4, 5 — Examples of the benzoyl group which may have 1 to 3 straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms as a substituent on a phenyl ring such as a trimethoxybenzoyl group. It can be.

In the present invention, among the above-mentioned carbostyril derivatives which are the active ingredient of the above-mentioned agent for treating multiple sclerosis, particularly preferred are, for example, 6- [4— (3,4-dimethoxybenzo). 1-piperazinyl] -1,3,4-dihydrocarbostyryl or a salt thereof.

Further, the salt of the carbostyril derivative represented by the above general formula (1) includes a pharmacologically acceptable acid addition salt. Specific examples of the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, and phosphorus. Organic acids such as acid, tartaric acid, citric acid, succinic acid, ethanesulfonic acid, p-toluenesulfonic acid, and benzoic acid can be exemplified.

The carbostyril derivative represented by the general formula (1) or a salt thereof, which is an active ingredient of the drug of the present invention, is usually used in the form of a general pharmaceutical preparation. Such a preparation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules Suppositories, injections (solutions, suspensions, etc.), eye drops and the like. These dosage forms are formulated by conventional formulation methods generally known in the art.

In the form of tablets, this part is used as a carrier. In the field, those conventionally known can be widely used. For example, excipients such as sugar, sucrose, sodium chloride, sodium sucrose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and gay acid; water, ethanol, propanol , Single syrup, glucose solution, starch solution, gelatin solution, carboxymethyl phenol resin, lacquer, methyl phenol resin, lysate Binders such as vinylpyrrolidone; dry starch, sodium alginate, powdered starch, powdered laminarane-sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, Disintegrators for sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc .; Disintegrators for sucrose, stearin, cocoa batata, hydrogenated oil, etc. Quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin, bentonite coco Adsorbents such as Loidal gay acid; lubricating agents such as purified talc, stearate, powdered boric acid, polyethylene glycol, and the like. Furthermore, tablets may be tablets coated with normal skin as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double-coated tablets or multilayer tablets. it can.

When molding into the form of pills, this part is used as a carrier. A wide variety of known substances can be used in the field, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, and evening meal; arabic gum powder, tragacanth powder, Binders such as gelatin and ethanol; disintegrators such as laminarancanthene can be used.

For molding into suppository form, widely known carriers can be used, such as polyethylene glycol, cocoa butter, higher alcohol, and higher alcohol. Esters, gelatin, semi-synthetic glyceride, etc. can be used (when prepared as injections, solutions, emulsions, suspensions, etc. are sterilized and isotonic with blood). Preferably, these liquids, emulsions, suspensions, and other forms can be used in the form of diluents commonly used in this field, for example. For example, water, ethyl alcohol, propylene glycol, ethoxylated iso-norethanol, polyoxylated iso-stanol, ethanol, etc. Reoxyethylene Sorbitan fatty acid ester In this case, the pharmaceutical preparation may contain a sufficient amount of salt, glucose, glycerin, etc. to prepare an isotonic solution. Ordinarily, an ordinary solubilizing agent, a buffer, a soothing agent, etc. may be added, such as sodium citrate, sodium acetate, sodium phosphate, etc. Triw Examples of the soothing agent include proforce hydrochloride and lidocaine hydrochloride.

Further, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation of the present invention, if necessary.

The amount of the compound represented by the general formula (1) contained as an active ingredient in the drug of the present invention is not particularly limited, and is appropriately selected from a wide range. Usually, it is suitably in the range of about 1 to 70% by weight, preferably about 1 to 30% by weight in the total composition.

The method of administration of the therapeutic agent for multiple sclerosis of the present invention thus obtained is not particularly limited, and is appropriately determined depending on various preparation forms, the age and sex of the patient, other conditions, the degree of the disease, and the like. You. For example, pharmaceutical preparations in the form of injections can be administered by intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal administration, and the like. It can also be administered intravenously by mixing it with a normal replacement fluid such as glucose or amino acid, if necessary. The pharmaceutical preparation of the present invention in a solid form such as a tablet, a pill, a granule, a capsule, or a liquid form for oral administration can be administered orally or enterally. Suppositories can be administered rectally. Eye drops can also be applied to the eyes.

The amount of the active ingredient of the present invention to be incorporated in each of the above dosage unit forms depends on the condition of the patient to which it is applied. Although it is not fixed depending on the dosage form and the like, it is generally appropriate to contain about 1 to 100 mg per dosage unit form. The daily dose can be appropriately selected according to the patient's symptoms, weight, age, gender, other conditions, and the like, and is not particularly limited. The carbostyril derivative (or salt thereof) of 1) is preferably selected from the range of about 0.5 to 30 mg Z kg per adult per day. It can be given once a day or divided into 3 to 4 times a day.

The preparation of the present invention is effective for improving various clinical symptoms of multiple sclerosis and for preventing and treating recurrence of multiple sclerosis. Example

Hereinafter, formulation examples and pharmacological test examples will be given in order to explain the present invention in more detail.

Formulation Example 1 Tablet

6 — [4 — (3, 4-Dimethoxy)

Benzoyl) 1 1-pipera dinyl]

— 3, 4 Hydrogen Norebostyril 5 mg Starch 13 2 mg Magnesium stearate 18 mg Lactose 4 5 mg

Tablets were produced at a mixing ratio of 200 mg per tablet according to a conventional method.

Formulation Example 2 Film-coated tablets

6 — [4 — (3, 4 — Dimethoxy

Benzo Nore) 1 1-Pipera Gininore

— 3, 4 — 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Cornstarch 30 g Magnesium stearate 2 g Hydrogel Glycine Propizoleme Chinoresorenose 10 g Polyethylene glycol 600 0 0 3 g Castor oil 40 g Metaanol 40 g

After mixing and polishing the above-mentioned active ingredient compound, Avicel, Cornstarch and magnesium stearate, the mixture is tableted with sugar coating R10 mm kine. The obtained tablets are coated with a phenolic coating agent composed of hydroxypropyl pilme tilsesolerose, polyethylene glycol 600, castor oil and methanol, and coated. 7 Lumco single tablets are manufactured.

Formulation Example 3 Tablet 6-C 4-(3, 4 — dimethoxy

Benzoinole) 1-Pipera Gininole]

— 3, 4 — Dihydrocarbostyline 15.0 g g Cyanate 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pull-out nick F — 6 8 30.0 g Sodium sodium lauryl sulfate 15, 0 g Polyvinyl pyrrolidone 15, 0 g Polyethylene glycol

(Canole Powax 1500) 45 g Polyethylene recall ''

(CanolepoWax 600 000) 450 g Cornstarch 300 g dried sodium lauryl sulfate 30 g dried magnesium stearate 30 g ethanol Suitable

The above active ingredient compound, citric acid, dicalcium lactate monophosphate, nickle F-68 and sodium raurylsulfate were mixed.

The above mixture was sieved with a No. 600 screen, and polyvinylpyrrolidone, canolebo wax 150 Wet granulation was carried out with an alcoholic solution containing Bolux 600. If necessary, alcohol was added to them to make the powder into a pasty mass. To this, cone starch was added and mixing was continued until uniform particles were formed. Next, the particles were passed through a No. 10 screen, placed in a tray, and dried in an oven at 100 ° C. for 12 to 14 hours. The resulting dried particles are sieved with a No. 16 screen, dried sodium lauryl sulfate and dried magnesium stearate are added, mixed, and mixed with a tableting machine to obtain the desired particles. It was compression molded into a shape.

The core was treated with varnish and talc was sprayed to prevent moisture absorption. An undercoat layer was coated around the core. A sufficient number of varnish coatings were taken for internal use. An additional subbing layer and a smooth coating were applied to make the tablets completely round and smooth. Color coating was performed until the desired color was obtained, and after drying, the resulting coated tablets were polished to prepare tablets of uniform gloss.

Pharmacological test example 1

As the test compound, 6- [4— (3,4-dimethylethoxybenzoyl) -1 1-piperazinyl] —3,4—dihydrorubostyril (hereinafter referred to as “compound 1”) was used. As described below, experiments that are considered animal models of multiple sclerosis Experimental allergic ence phalomyelitis; EAE: Paterson, PY, Fed. Proc., 41, 2569-2576 (1982); Paterson, PY, Immunological D i seases, 3rd edn., Little, Brown & Co., Boston, MA.pp. 1400-1435 (1978); Alvord, EC Jr., Progress in C1 inical and Biological Research, 148. Alan R. shi iss, New York, NY, pp. 523-537 (1984)) Using an animal model, the inhibitory effect of a test compound on clinical score was evaluated by Koh et al. (Koh, CS, et al., Cell Immunology, 107, 52-63 (1987)). The evaluation was performed according to the above method.

The above animal model of EAE induces EAE by sensitizing (immunizing) animals with a central nervous tissue (eg, guinea pig spinal cord) and an adjuvant. On day 0, symptoms accompanied by paralysis of the tail and lower limbs appear. If a monoremot spinal cord (Guinea-Pig Spinal Cord; GPSC) homogenate and an adjuvant containing a high concentration of Mycobacterium Tube rculosis (T) are used, about 40 days after immunization Is a model for chronic progressive multiple sclerosis that repeats 2-3 onsets and recovery over a period of time (Chabannes, D., et al., J. Autoimmunity, 5, 199-211 (1992) ).

(1) Preparation of animals and experimental materials 1) A 0.5% CMC solution (carboxy-methyl-cellulose solution) was used as the control. The solution was prepared by using a CMC (Serogen F—SB (Lot No. 154455), manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.) on an electronic balance (ER-182A; manufactured by Sartorius). After weighing 5.0 g, transfer to a plastic cylinder and dissolve in distilled water for injection (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) at 4 ° C for 24 hours to obtain a final concentration of 0.5%. After preparation, the solution was sterilized in an autoclave and stored at 4 ° C until use.

2) After weighing the bulk of Compound 1 and transferring it to an agate bowl, suspending uniformly with a small amount of 0.5% CMC solution, diluting with 0.5% CMC solution, and final concentration of Compound 1 Was adjusted to a concentration of 60 mg Zm 1. It was dispensed into sterile centrifuge tubes and stored at 4 ° C protected from light until use.

3) The guinea pig spinal cord (GPSC) homogenate used as an immunogen is a 9- to 10-week-old (500-600 g) male heart-shaped Mosolemot (Charles River Japan). (Purchased from one company) Prepared using all 20 animals. Guinea pigs were euthanized by cervical dislocation under light ether anesthesia, the meninges and blood vessels were detached from the spinal cord, and the excised spinal cord was transferred to an ice-cooled dish. The extirpated spinal cords of the 10 quintiles were weighed together, and weighed to 1 g of GPSC in a potter homogenizer. On the other hand, 1 m1 of cold saline (Otsuka Pharmaceutical Factory) was added, and a homogenate was prepared using a homogenate preparation rotor (Ikemoto Rika Kogyo) under ice-cooling (GPSC). The concentration was 500 mg / ml). The solution was dispensed into 3 to 4 mlf PPP tubes and stored frozen at 120 ° C.

4) An adjuvant solution containing M. tuberculosis (MT) was prepared using a commercially available complete adjuvant solution containing M. tuberculosis (M. tuberculosis killed H37 Ra concentration lmg Zml; catalog number 311) 3 — 60-5: manufactured by Difco Inc. l O ml Z bottle, and further killed tuberculosis H 37 Ra (catalog number 3 1 1 4 — 3 3 — 8: made by Difco Inc.) And added 15 mg. After sealing with Raffinorem, mix well by inverting, and then suspend uniformly to obtain a final MT concentration of 2.

It was adjusted to 5 rag / m1.

5) The GPSC homogenate prepared in 3) above and the adjuvant solution containing killed M. tuberculosis prepared in 4) above were mixed at a ratio of 1: 1 to the two glass syringes connected to the three-way stopcock. The resulting emulsion was transferred and repeatedly mixed until a uniform emulsion was formed, and the resulting emulsion solution was used as an immunization emulsion.

6) 10-week-old female Louis as an animal for the experiment

(Lewis) type rat (SPF: purchased from Nippon Charles Rinoku Co., Ltd.) was used. Buy 100 animals at 9 weeks of age, 1 week After acclimatization, a total of 60 animals in each of 20 mice in each group, 4 cages and 3 groups were extracted for the present test by random sampling by stratification using body weight as an index.

(2) animal model of multiple sclerosis

Ten week old female Louis rats weighing 180-200 g were subjected to the study. Rats were allowed free access to water and normal feed orally.

The induction of experimental allergic monoencephalomyelitis (EAE) as an animal model for multiple sclerosis was as follows. Immediately, the immunized emulsion prepared in (1) to (5) above was put on a foot pad of a rat under light ether anesthesia with a 23-gauge injection needle and a 1.0-m1 glass bottle. A total of 0.2 ml {(50 mg as GPSC + 250 as MT)} of 0.1 ml was injected intradermally using a syringe. After immunization, the animals were reared in the cage of 5 animals. The rat develops allergic encephalomyelitis symptoms around 10 days after immunization, and repeats relapse and remission, similar to human clinical symptoms, and therefore multiple sclerosis. Animal model.

(3) Examination of therapeutic effect of compound 1 of the present invention on multiple sclerosis and prevention of recurrence

1) Administration of the compound of the present invention to a rat

(1) A suspension of the present compound 1 prepared in (1) 2) ′, Mix well by inverting the tube immediately before administration to the rat, take it into a 1 ml or 2.5 ml syringe (manufactured by Terumo Corporation), and use an oral tube for rat. 0.5 ml was administered by oral gavage to the body weight of 100 g of the rat. The dose was determined for each animal based on the body weight on the day automatically input to the computer. The group to which the 0.5% CMC solution was administered as the control group was administered in the same manner.

Experiments on animal models of multiple sclerosis

• The control group to which the CMC solution was administered every day after immunization. 'The CMC solution was administered from 1 to 9 days after immunization, and 30 days after the onset of EAE, 30 mg of the compound 1 was administered. mg Z kg / day group (Compound 1 was administered immediately after the first symptom onset) and

'' Administer CMC solution from 1 to 16 days after immunization, and then compound 1 at a rate of 30 O mg Z kg Z day from day 17 when symptoms recover once and begin to worsen again Administered group (group administered Compound 1 shortly before the onset of the second symptom)

In each of the three groups, oral administration was performed once daily for up to 37 days after immunization, using 20 animals in each group.

2) Rat weight, blood cell measurement, thymus weight, spleen weight measurement and symptom observation (scoring judgment)

From the test start date (immunization date) to the test end date (dissection date) Observation of body weight and symptoms (score judgment) was performed once a day. The body weight was measured with an electronic balance (Sartorius; LC-4200: manufactured by Sartorius) and connected to a personal computer.

(TOSHIBA J3100: manufactured by Toshiba), and at the same time, the dose for each individual was determined and displayed.

The scoring of symptoms was evaluated according to the evaluation criteria of Koh et al. (Koh, CS, et al., Cell Immunology, 107, 52-63 (1987)). That is, the rat's symptoms in each group were observed every day, the scores were determined for the rat tail and both hind limbs, and the total was recorded on a score record sheet. The score was 0 for asymptomatic, 0.25 for halfway relaxation, and 0.5 for complete relaxation of the entire tail for the tail, and 0 for asymptomatic and 1 for walking impairment in the hind limbs. Incomplete paralysis of both hind limbs and complete paralysis of one hind limb were evaluated as 2.0, and complete paralysis of both hind limbs was evaluated as 3.0. The deaths during the study were excluded from the statistical processing for scoring.

3) Statistical processing method

All statistical analyzes were performed with the SAS system (SAS Institute Japan, Ver. 6.11).

The body weight was measured using the control group as a control and the measured values for the group that received Compound 1 immediately after the onset of the first symptom and the group that received Compound 1 immediately before the onset of the second symptom. Use Differences in response over time were tested by repeated measures (Repeated esurements) and performed at 5% and 1% significance levels.

Observation of symptoms (score evaluation of symptoms)

The entire study period was divided into the first half and the second half according to the change in the clinical score of the control group. That is, at the time of the best recovery between two peaks (Chabannes, D., et al., J. Autoim raunity, 5, 199-211 (1992)), the score is divided into the first half and the second half. The analysis was performed in three periods: the whole period, the first half, and the second half. More specifically, the score judgment results of the symptoms of each individual in each period are integrated, and the average integrated clinical score (Integrated Clinical Score) is calculated for each group (Branisteanu, DD, et al., J. Neuroimmunolog y, 61, 151-160 (1995); Martin, D., et al., J. Neuroimmunology, 61-241-245 (1995)) As a control, a two-sided Dunnett-test was used to test the significance level at 5% and 1%. The score is expressed as the mean score and the standard error.Chemocyte measurement, thymus weight and spleen weight are analyzed by one-way analysis of variance, followed by two-sided Dunnett-test using the control group as a control. Test and conduct significance level at 5% and 1% Shi / ο

The results of symptom score determination and changes in body weight are shown in FIGS. 1, 2, and 3, respectively.

In FIG. 1, the vertical axis represents the average clinical score, and the horizontal axis represents the administration period (days) after immunization.

“―〇” is the result of the control (CMC solution only) group, “Ikukuni” is the result of the group that started administration of compound 1 on day 17 after immunization, and

"1-1-1" is the result of the group that started administration on day 10 after immunization of compound 1.

Are respectively shown.

In Figure 2, the vertical axis represents the average cumulative clinical score (the average of the cumulative clinical scores from 0 to 38), and the horizontal axis represents the cumulative clinical score.

(A): control (CMC solution only) group,

(B): a group in which administration of compound 1 was started on day 17 after immunization and

(C): The groups in which administration of compound 1 was started on day 10 after immunization, respectively.

In Fig. 3, the vertical axis shows the change in daily body weight, and the horizontal axis shows the administration period (days) after immunization.

“―〇” is the result of the control (CMC solution only) group, and “Ichikoku-” is the administration of compound 1 on day 17 after immunization. Group results and

"1-1-1" is the result of the group that started administration of compound 1 from day 10 after immunization.

Are respectively shown.

From the above results, the following is clear. That is,

As can be seen from Fig. 2, the compound 1 administration group showed a significant decrease in the average cumulative clinical score (P <0.01) compared to the control group, ie, An improvement effect was observed. In addition, as shown in Fig. 3, the changes in body weight corresponded to the changes in symptom score judgment in Fig. 1, and the compound 1 administration group compared with the control group, as shown in Fig. 3. As a result, an improvement tendency was recognized. Furthermore, as shown in FIG. 1, it can be seen that Compound 1 improves the symptom and suppresses the onset of the second symptom by administration immediately after the onset of the first symptom. The group to which Compound 1 was administered immediately before the onset of the second symptom suppressed the recurrence of the symptom. To date, no drug has been known to produce a clear effect when administered after the onset of symptoms.Compound 1 is used to prevent recurrence of relapsed / recoverable and chronic progressive multiple sclerosis, which are difficult to treat in clinical practice. It is clear that therapeutic effects on various clinical symptoms can be expected. Industrial applicability According to the present invention, there is provided a remedy for multiple sclerosis comprising at least one active ingredient selected from the carbostyril derivatives represented by the general formula (1) and salts thereof, which is used in the pharmaceutical field. It improves various clinical symptoms of multiple sclerosis, which is difficult to treat, and is useful for preventing and treating recurrence of multiple sclerosis.

Claims

The scope of the claims

1. The following general formula (1):

[In the formula, R represents a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring. The carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton indicates a single bond or a double bond. ]

A therapeutic agent for multiple sclerosis, comprising an effective amount of at least one selected from the carbostyril derivative represented by the formula (I) and a salt thereof, and a pharmaceutically acceptable carrier.

Is a benzoyl group which may have 1 to 3 straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring. For multiple sclerosis.

3. The carbostyril derivative is 6- [4— (3,4—dimethoxybenzene)] 1,3-pipera dininole] 1,3,4—dihydrocarbostyril or a salt thereof Claim 1 For multiple sclerosis.

4. A method for treating multiple sclerosis, comprising administering to a patient at least one effective amount selected from the carbostyril derivative according to claim 1 and a salt thereof.

5. The method according to claim 4, wherein R is a benzoyl group which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring. For treating multiple sclerosis in Japan.

6. The multiple occurrence according to claim 4, wherein the carbostyril derivative is 6- [4- (3,4-dimethoxybenzoinole) -1-1-pipera-dininole] -3,4-dihydrocarbostyril or a salt thereof. How to treat multiple sclerosis.

7. Use of at least one selected from the carbostyril derivatives and salts thereof according to claim 1 for the manufacture of a therapeutic agent for multiple sclerosis.

8 .- is a benzoyl group which may have 1 to 3 straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring. For the manufacture of an agent for treating multiple sclerosis.

9. The method according to claim 7, wherein the carbostyril derivative is 6- [4— (3,4-dimethoxybenzoyl) -11-piperazinyl] -13,4—dihydroxycarbostyril or a salt thereof. Use for the manufacture of a multiple sclerosis therapeutic agent.